Taste masked liquid pharmaceutical compositions

ABSTRACT

This invention is directed to a taste masked liquid pharmaceutical composition comprising a pharmaceutically active agent and a taste masking composition. In particular, the taste masking composition comprises a taste masking effective amount of an artificial sweetener.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of provisional application Ser. No.60/273,472, filed 5 Mar. 2001, which is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to novel taste masked liquidpharmaceutical compositions for oral administration. In particular, thisinvention relates to taste masked liquid pharmaceutical compositionscomprising a pharmaceutically active agent and a taste maskingcomposition. More particularly, the taste masking composition comprisesa taste masking effective amount of an artificial sweetener.

BACKGROUND OF THE INVENTION

Orally administered drugs are provided to the patient in many dosageforms, including solid forms such as capsules, caplets or tablets andliquid forms such as solutions, syrups, emulsions or suspensions.Pharmaceutically active agents administered in solid dosage form areusually intended to be swallowed whole. The disagreeable taste of thedrug is generally not of concern when formulating oral solid dosageforms, because the pharmaceutical's taste can be easily masked with anexterior coating.

Children, older persons, and many other persons including disabled orincapacitated patients often have trouble swallowing tablets orcapsules. In these situations, it is desirable to provide the drugeither in a chewable solid form or a liquid form. For many patients,including pediatric and geriatric patients, a liquid oral dosage form ispreferred over a chewable dosage form. A liquid dosage is especiallypreferred for this class of patients because of the ease with which itmay be swallowed. Additionally, patients may be more inclined to complywith their medication instruction if the dosages are easier to ingest.

Many liquid pharmaceutical compositions formulated for use by pediatricor geriatric patients are often prepared by grinding a tablet dosageform into a powder and mixing the powder with a diluent. Such aformulation often allows much of the drug to remain undissolved, therebyaffecting the therapeutic concentration of drug in the composition. Inaddition, the powder exposes the unpleasant tasting pharmaceuticallyactive agent, thus further requiring a means of masking the taste. It isreadily understood that such compositions are impractical and may resultin underdosing or overdosing a patient.

A common formulation problem associated with liquid pharmaceuticaldosage forms (such as solutions (including syrups) or suspensions) ismasking the disagreeable taste that a pharmaceutically active agent mayoften manifest when administered in a liquid dosage form. Many activeingredients, such as antibiotics, possess a strong, unpleasant andbitter taste. Unpleasant and bitter tasting antibiotics include gyraseinhibitors; particularly, those of the naphthyridone-carboxylic acid andquinolone-carboxylic acid types; more particularly, those selected fromlevofloxacin, ciprofloxacin, norfloxacin, ofloxacin or enoxacin.

In view of these difficulties, it would be desirable to develop aready-to-use taste masked liquid pharmaceutical dosage form, inparticular, a solution or suspension. More particularly, there exists aneed for a taste masked suspension dosage form that minimizessedimentation of the pharmaceutically active agent, provides uniformdistribution of the active agent and has a palatable taste.

An object of the present invention is to provide a taste masked liquidpharmaceutical composition comprising a pharmaceutically active agentand a taste masking composition.

An object of the present invention is to provide a taste masked liquidpharmaceutical composition comprising a pharmaceutically active agentand a taste masking composition wherein the taste masking compositioncomprises a taste masking effective amount of an artificial sweetener.

An object of the present invention is to provide a taste masked liquidpharmaceutical composition wherein the pharmaceutically active agent isbitter tasting.

An object of the present invention is to provide a taste masked liquidpharmaceutical composition wherein the bitter tasting pharmaceuticallyactive agent is an antibiotic.

An object of the present invention is to provide a taste masked liquidpharmaceutical composition wherein the bitter tasting antibiotic islevofloxacin.

An object of the present invention is to provide a taste masked liquidpharmaceutical composition wherein the taste masking effective amount ofan artificial sweetener masks a bitter taste.

An object of the present invention is to provide a taste masked liquidpharmaceutical composition wherein the taste masking compositioncomprises a taste masking effective amount of sucralose.

An object of the present invention is to provide a taste masked liquidpharmaceutical composition wherein the taste masking composition furthercomprises a taste masking effective amount of an artificial sweetenerand at least one flavoring agent.

An object of the present invention is to provide a taste masked liquidpharmaceutical composition wherein the taste masking composition furthercomprises a taste masking effective amount of an artificial sweetener,at least one flavoring agent, an optional sweetening agent and anoptional debittering agent or mixtures thereof.

SUMMARY OF THE INVENTION

The present invention provides a taste masked liquid pharmaceuticalcomposition comprising a pharmaceutically active agent and a tastemasking composition.

The present invention provides a taste masked liquid pharmaceuticalcomposition comprising a pharmaceutically active agent and a tastemasking composition wherein the taste masking composition comprises ataste masking effective amount of an artificial sweetener.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the pharmaceutically active agent is bitter tasting.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the bitter tasting pharmaceutically active agent isan antibiotic.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the bitter tasting antibiotic is levofloxacin.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the taste masking effective amount of an artificialsweetener masks a bitter taste.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the taste masking composition comprises a tastemasking effective amount of the artificial sweetener sucralose.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the taste masking composition further comprises ataste masking effective amount of an artificial sweetener and at leastone flavoring agent.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the taste masking composition further comprises ataste masking effective amount of the artificial sweetener sucralose andat least one flavoring agent.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the taste masking composition further comprises ataste masking effective amount of an artificial sweetener, at least oneflavoring agent, an optional sweetening agent and an optionaldebittering agent or mixtures thereof.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the taste masking composition further comprises ataste masking effective amount of the artificial sweetener sucralose, atleast one flavoring agent, an optional sweetening agent and an optionaldebittering agent or mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a taste masked liquid pharmaceuticalcomposition comprising a pharmaceutically active agent and a tastemasking composition.

The present invention provides a taste masked liquid pharmaceuticalcomposition comprising a pharmaceutically active agent and a tastemasking composition wherein the, taste masking composition comprises ataste masking effective amount of an artificial sweetener.

In an embodiment of the present invention, the pharmaceutically activeagent is bitter tasting and includes, but is not limited to, thoseselected from antibiotics, analgesics, anti-inflammatory drugs,antihistamines, antibacterials, antimicrobials, decongestants,anti-depressants, anti-psychotics, antivirals, oncolytics, vaccines,antiepileptics, anti-asthma compounds or antispasmodics.

In an embodiment of the present invention, the bitter tastingpharmaceutically active agent is an antibiotic and includes, but is notlimited to, those selected from a naphthyridone-carboxylic acid typeantibiotic, a quinolone-carboxylic acid type antibiotic, a cephalosporintype antibiotic, a macrolide type antibiotic or a penicillin typeantibiotic and the like.

In a preferred embodiment of the present invention, the bitter tastingpharmaceutically active agent is a quinolone-carboxylic acid antibioticand includes, but is not limited to, those selected from levofloxacin,ciprofloxacin, norfloxacin, ofloxacin or enoxacin.

In a more preferred embodiment of the present invention, the bittertasting quinolone-carboxylic acid antibiotic is levofloxacin (marketedunder the tradename LEVAQUIN®), a compound having the CAS (ChemicalAbstracts Society) Registry Number: 100986-85-4 and the CAS Index Name:(3S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylicacid.

The pharmaceutically active agent is present in the composition in atherapeutically effective amount, which amount produces the desiredtherapeutic response and can be readily determined by one skilled in theart. In determining such an amount, the particular compound beingadministered, the bioavailability characteristics of thepharmaceutically active agent, the dose regimen, the method ofadministration, the age and weight of the patient and other factors mustbe considered.

In an embodiment of the present invention, the bitter tastingpharmaceutically active agent is a therapeutically effective amount oflevofloxacin; wherein the therapeutically effective amount has a rangeof from about 1 gram to about 5 grams of levofloxacin per 100 mL. In afurther embodiment, the therapeutically effective amount has a range offrom about 2.5 grams to about 5 grams of levofloxacin per 100 mL. Inpreferred embodiments of the present invention, the therapeuticallyeffective amount is selected from about 1 gram of levofloxacin per 100mL, about 2.5 grams of levofloxacin per 100 mL or about 5 grams oflevofloxacin per 100 mL.

In an embodiment of the present invention, the liquid pharmaceuticalcomposition is a solution, syrup or suspension for oral administrationto adult and pediatric patients comprising a therapeutically effectiveamount of a bitter tasting pharmaceutically active agent and a tastemasking composition.

In an embodiment of the present invention, the taste masking compositioncomprises a taste masking effective amount of an artificial sweetener.

In general, the total amount of the taste masking composition present ina taste masked liquid pharmaceutical composition comprises from about 70to 90% weight to volume of the total liquid composition; preferably,about 80% weight to volume. The present invention is not limited to thisamount but rather to a taste masking effective amount, whereby the tasteof the bitter tasting pharmaceutically active agent is masked and theliquid pharmaceutical composition is palatable to the intended consumer,such as a pediatric or adult patient in need thereof.

For example, the use of a highly intense artificial sweetener wouldrequire a lower amount of a sweetening agent compared to the use of asugar sweetener to achieve a taste masking effective amount. The tastemasking effective amount required varies with the amount of thepharmaceutically active agent used and the intensity of the unpalatabletaste.

In the present invention, we have surprisingly discovered that a tastemasking effective amount of an artificial sweetener unexpectedly masksthe taste of a bitter tasting pharmaceutically active agent.

Artificial sweeteners that may be used in the present invention include,and are not limited to, aspartame, acesulfame potassium, cyclamate,saccharin, saccharin sodium, sucralose or mixtures thereof. The tastemasking effective amount of an artificial sweetener is that amountwhereby the taste of the bitter tasting pharmaceutically active agent ismasked and the liquid pharmaceutical composition is palatable.

Aspartame is used as a table-top sweetener and in beverage and foodproducts and pharmaceutical and vitamin preparations to enhance flavorsystems and to mask some unpleasant taste characteristics.Comparatively, aspartame has approximately 180-200 times the sweeteningpower of sucrose. The taste masking effective amount of aspartame has arange of from about 0.15 to about 8 grams per 100 mL.

Acesulfame potassium is used as a table-top sweetener and in cosmetics,beverage and food products and pharmaceutical and vitamin preparationsto enhance flavor systems and to mask some unpleasant tastecharacteristics. Comparatively, acesulfame potassium has approximately180-200 times the sweetening power of sucrose. The taste maskingeffective amount of acesulfame potassium has a range of from about 0.15to about 8 grams per 100 mL.

Cyclamate is used as a table-top sweetener and in beverage and foodproducts. Comparatively, cyclamate has approximately 30 times thesweetening power of sucrose. The taste masking effective amount ofcyclamate has a range of from about 1 to about 50 grams per 100 mL.

Saccharin is used to enhance flavor systems and to mask some unpleasanttaste characteristics and has approximately 500 times the sweeteningpower of sucrose. The taste masking effective amount of saccharin has arange of from about 0.08 to about 3 grams per 100 mL.

Saccharin sodium is considerably more soluble in water than saccharin,is used more frequently in pharmaceutical formulations and hasapproximately 300 times the sweetening power of sucrose. The tastemasking effective amount of saccharin sodium has a range of from about0.1 to about 5 grams per 100 mL.

Sucralose (marketed under the tradename SPLENDA®) is a compound havingthe CAS Registry Number: 56038-13-2 and the CAS Index Name:1,6-dideoxy-b-D-fructofuranosyl-4-chloro-4-deoxy-α-D-galactopyranosideand is characterized as an intensely sweet, trichlorinated carbohydrate,structurally similar to sucrose, having approximately 600 times thesweetening power of sucrose.

Mixtures of artificial sweeteners, such as a ratio of 10 parts cyclamateto 1 part saccharin, have also been found to have synergistic sweeteningproperties and improve taste characteristics.

A preferred embodiment of the taste masking composition comprises ataste masking effective amount of the artificial sweetener sucralose.The amount of sucralose used causes sucralose to mask the taste of thebitter tasting pharmaceutically active agent. The present inventionthereby intends that sucralose be used in a taste masking effectiveamount in a plurality of liquid pharmaceutical compositions wherein thepharmaceutically active agent is bitter tasting to make the liquidpharmaceutical compositions palatable.

Preferably, the taste masking effective amount of sucralose has a rangeof from about 0.05 to about 2.5 grams per 100 mL. More preferably, thetaste masking effective amount of sucralose has a range of from about0.45 to about 1.7 grams per 100 mL. More preferably, the taste maskingeffective amount of sucralose is about 1 gram per 100 mL.

Another embodiment of the taste masking composition further comprises ataste masking effective amount of an artificial sweetener and at leastone flavoring agent.

The flavoring agent used is of the type and amount desired to enhancethe palatability of the particular liquid pharmaceutical composition tothe intended consumer. Flavoring agents that may be used in the presentinvention include, and are not limited to, natural flavors, naturalfruit flavors, artificial flavors, artificial fruit flavors, flavorenhancers or mixtures thereof. Natural flavors, artificial flavors ormixtures thereof include, and are not limited to, mint (such aspeppermint or spearmint), menthol, cinnamon, vanilla, artificialvanilla, chocolate, artificial chocolate or bubblegum. Natural fruitflavors, artificial fruit flavors or mixtures thereof include, and arenot limited to, cherry, grape, orange, strawberry or lemon. Flavorenhancers include, and are not limited to, citric acid. Althoughflavoring agents are generally provided as a minor component of thetaste masking composition in amounts effective to provide a palatableflavor to the liquid pharmaceutical composition, the addition of atleast one flavoring agent is preferred; and, more preferably, up to twoflavoring agents may be employed. A flavoring agent used in the tastemasking composition has a range of from about 0.02 to about 0.06 gramsper 100 mL. Preferably, a flavoring agent is present in a range of fromabout 0.03 to about 0.04 grams per 100 mL.

Another embodiment of the taste masking composition further comprises ataste masking effective amount of an artificial sweetener, at least oneflavoring agent, an optional sweetening agent and an optionaldebittering agent or mixtures thereof.

Optional sweetening agents include, but are not limited to, sugarsweeteners such as monosaccharides, disaccharides and polysaccharides.Examples of suitable sugar sweeteners include but are not limited toxylose, ribose, glucose, mannose, galactose, fructose, dextrose,sucrose, maltose, partially hydrolyzed starch (such as maltitol syrup)or corn syrup solids and sugar alcohols such as sorbitol, xylitol,mannitol, glycerin and combination thereof. Preferably, the type ofglycerin used is U.S.P. grade. Preferred as a sugar sweetener is highfructose corn syrup. The amount of sugar sweetener used in the tastemasking composition will vary depending on the degree of palatabilitydesired for the liquid pharmaceutical composition. Generally the totalamount of sugar sweetener used has a range of from 0 to about 120 gramsper 100 mL. Preferably, the amount of sugar sweetener used has a rangeof from about 50 grams to about 110 grams per 100 mL.

Optional sweetening agents include artificial sweeteners used inaddition to sugar sweeteners. Preferably, other artificial sweetenersinclude, and are not limited to, aspartame, acesulfame potassium,cyclamate, saccharin, saccharin sodium, sucralose or mixtures thereof.The optional amount of artificial sweeteners used in the taste maskingcomposition will vary depending on the degree of palatability desiredfor the liquid pharmaceutical composition. Generally, the amount of anoptional artificial sweetener used in the taste masking composition hasa range of from about 0 to about 1.5 grams per 100 mL.

In general, one optional debittering agent is employed in a tastemasking composition of the present invention. Optional debitteringagents include, and are not limited to, natural debittering agents,artificial debittering agents or debittering agents which inhibit achemosensory response in the mouth or nose or mixtures thereof.Debittering agents for use in the present invention are commerciallyavailable, such as those marketed under the names Prosweet Fla. N&A K(by Virginia Dare), Bitterness Modifier 36734 (by Bush, Boake and Allen,Inc.), Natural Taste Masker 501.441/A and Special Taste Masker Compound501.437/A (by Firmenich, Inc.), and may be identified by those skilledin the art.

Accordingly, a natural debittering agent, artificial debittering agentor chemosensory response inhibitor agent present in the taste maskingcomposition has a range of from about 0 grams to about 1 gram per 100mL. Preferably, a debittering agent has a range of from about 0.01 toabout 0.2 grams per 100 mL. More preferably, a debittering agent has arange of from about 0.03 to about 0.05 grams per 100 mL.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the pharmaceutical composition is a suspensioncomprising a pharmaceutically active agent and a taste maskingcomposition.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the pharmaceutical composition is a suspensioncomprising a pharmaceutically active agent and a taste maskingcomposition wherein the taste masking composition comprises a tastemasking effective amount of an artificial sweetener.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the pharmaceutical composition is a suspensioncomprising a bitter tasting pharmaceutically active agent and a tastemasking composition.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the pharmaceutical composition is a suspensioncomprising a bitter tasting antibiotic and a taste masking composition.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the pharmaceutical composition is a suspensioncomprising the bitter tasting antibiotic levofloxacin and a tastemasking composition.

An embodiment of the invention is a taste masked liquid pharmaceuticalsuspension wherein the taste masking effective amount of an artificialsweetener masks a bitter taste.

An embodiment of the invention is a taste masked liquid pharmaceuticalsuspension wherein the taste masking composition comprises a tastemasking effective amount of the artificial sweetener sucralose.

An embodiment of the invention is a taste masked liquid pharmaceuticalsuspension wherein the taste masking composition further comprises ataste masking effective amount of an artificial sweetener and at leastone flavoring agent.

An embodiment of the invention is a taste masked liquid pharmaceuticalsuspension wherein the taste masking composition further comprises ataste masking effective amount of the artificial sweetener sucralose andat least one flavoring agent.

An embodiment of the invention is a taste masked liquid pharmaceuticalsuspension wherein the taste masking composition further comprises ataste masking effective amount of an artificial sweetener, at least oneflavoring agent, an optional sweetening agent and an optionaldebittering agent or mixtures thereof.

An embodiment of the invention is a taste masked liquid pharmaceuticalsuspension wherein the taste masking composition further comprises ataste masking effective amount of the artificial sweetener sucralose, atleast one flavoring agent, an optional sweetening agent and an optionaldebittering agent or mixtures thereof.

An embodiment of the invention is a taste masked liquid pharmaceuticalsuspension wherein the suspension comprises a polysaccharide gum and amicrocrystalline cellulose or a carboxymethylcellulose or a mixturethereof.

An embodiment of the invention is a taste masked liquid pharmaceuticalsuspension wherein the suspension comprises a polysaccharide gumselected from a high molecular weight polysaccharide gum and amicrocrystalline cellulose or a carboxymethylcellulose selected fromcarboxymethylcellulose or a metal salt thereof, wherein the metal saltis selected from calcium, sodium or potassium.

An embodiment of the invention is a taste masked liquid pharmaceuticalsuspension wherein the suspension comprises a high molecular weightpolysaccharide gum selected from xanthan, tragacanth, guar or carageenanand a microcrystalline cellulose or a carboxymethylcellulose selectedfrom carboxymethylcellulose or a metal salt thereof, wherein the metalsalt is selected from calcium, sodium or potassium.

An embodiment of the invention is a taste masked liquid pharmaceuticalsuspension wherein the suspension comprises a xanthan gum and a mixtureof microcrystalline cellulose and sodium carboxymethylcellulose.

The preferred polysaccharide gum for use in a taste masked liquidpharmaceutical suspension is xanthan gum, a high molecular weightpolysaccharide gum produced by Xanthomonas campestris. Techniques andstrains for producing this polysaccharide are described in U.S. Pat.Nos. 4,752,580 and 3,485,719 (the disclosures of which are herebyincorporated by reference). Preferably, the gum used in the presentinvention should have a viscosity in a 1% salt solution of from about1000 to about 1700 cP (mPa-sec), as measured at 25° C. with an LV modelBrookfield Synchro-Lectric viscometer at 60 rpm, no. 3 spindle.

Preferably, the amount of xanthan gum present has a range of from about0.05 to about 0.25 gram per 100 mL. More preferably, xanthan gum has arange of from about 0.09 to about 0.20 gram per 100 mL. Most preferably,the amount of xanthan gum present is about 0.14 gram per 100 mL.

A preferred embodiment of the invention is a taste masked liquidpharmaceutical suspension wherein the suspension comprises apolysaccharide gum and a mixture of microcrystalline cellulose and acarboxymethylcellulose.

The preferred mixture of microcrystalline cellulose and acarboxymethylcellulose comprises a commercially available driedcoprecipitated microcrystal of cellulose in a mixture with sodiumcarboxymethylcellulose. Sodium carboxymethylcellulose is commonly usedas the coprecipitate in microcrystalline cellulose. It is preferablethat sodium carboxymethylcellulose be present in the range of from about8 weight percent to about 19 weight percent of the total weight of themixture of microcrystalline cellulose and sodium carboxymethylcellulose.Preferred microcrystalline cellulose and sodium carboxymethylcellulosemixtures have sodium carboxymethylcellulose present in the range of fromabout 8 to about 14 weight percent. These mixtures are commerciallyavailable from FMC under the trademark Avicel® CL-611, Avicel® RC-581and Avicel® RC-591. Avicel® RC-591 is the preferred mixture ofmicrocrystalline cellulose and sodium carboxymethylcellulose for use inthe suspension and contains about 8.3 to about 13.8 weight percentsodium carboxymethylcellulose, with the remainder being microcrystallinecellulose.

Preferably, the mixture of microcrystalline cellulose and sodiumcarboxymethylcellulose is present in a range of from about 0.4 to about1.0 gram per 100 mL. Preferably, the mixture has a range of from about0.6 to about 0.8 gram per 100 mL. More preferably, about 0.7 gram per100 mL of the mixture is present.

A preferred embodiment of the suspension comprises a weight ratio ofxanthan gum to the mixture of microcrystalline cellulose and sodiumcarboxymethylcellulose wherein the weight ratio is maintained in a rangeof between about 1:4 to 1:8. Preferably, the weight ratio is maintainedin a range of about 1:6.

A preferred embodiment of the suspension comprises limiting the amountof water present to that amount necessary to hydrate the xanthan gum andthe mixture of microcrystalline cellulose and sodiumcarboxymethylcellulose while providing a sufficient aqueous base toimpart the desired degree of viscosity.

The total amount of water present in the suspension has a range of fromabout 5 to about 60 grams per 100 mL. Preferably, water has a range offrom about 10 to about 30 grams per 100 mL. More preferably, water has arange of from about 10 to about 20 grams per 100 mL. Most preferably,about 15 grams of water is present per 100 mL of suspension.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the pharmaceutical composition is a solutioncomprising a pharmaceutically active agent and a taste maskingcomposition.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the pharmaceutical composition is a solutioncomprising a pharmaceutically active agent and a taste maskingcomposition wherein the taste masking composition comprises a tastemasking effective amount of an artificial sweetener.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the pharmaceutical composition is a solutioncomprising a bitter tasting pharmaceutically active agent and a tastemasking composition.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the pharmaceutical composition is a solutioncomprising a bitter tasting antibiotic and a taste masking composition.

An embodiment of the invention is a taste masked liquid pharmaceuticalcomposition wherein the pharmaceutical composition is a solutioncomprising the bitter tasting antibiotic levofloxacin and a tastemasking composition.

An embodiment of the invention is a taste masked liquid pharmaceuticalsolution wherein the taste masking effective amount of an artificialsweetener masks a bitter taste.

An embodiment of the invention is a taste masked liquid pharmaceuticalsolution wherein the taste masking composition comprises a taste maskingeffective amount of the artificial sweetener sucralose.

An embodiment of the invention is a taste masked liquid pharmaceuticalsolution wherein the taste masking composition further comprises a tastemasking effective amount of an artificial sweetener and at least oneflavoring agent.

An embodiment of the invention is a taste masked liquid pharmaceuticalsolution wherein the taste masking composition further comprises a tastemasking effective amount of the artificial sweetener sucralose and atleast one flavoring agent.

An embodiment of the invention is a taste masked liquid pharmaceuticalsolution wherein the taste masking composition further comprises a tastemasking effective amount of an artificial sweetener, at least oneflavoring agent, an optional sweetening agent and an optionaldebittering agent or mixtures thereof.

An embodiment of the invention is a taste masked liquid pharmaceuticalsolution wherein the taste masking composition further comprises a tastemasking effective amount of the artificial sweetener sucralose, at leastone flavoring agent, an optional sweetening agent and an optionaldebittering agent or mixtures thereof.

The taste masked liquid pharmaceutical composition of the presentinvention may optionally contain pH stabilizers (such as, but notlimited to, citric acid, ascorbic acid, potassium phosphate or sodiumphosphate), pH buffers (such as, but not limited to, citric acid,ascorbic acid, potassium phosphate or sodium phosphate), wetting agents(such as, but not limited to, sodium laurel sulfate or docusate sodium),preservatives, coloring agents (such as, but not limited to, dyes, lakedyes or natural coloring), defoaming agents (such as, but not limitedto, simethicone), surfactants (such as, but not limited to, sorbitanoleate ester or polyoxyethylene sorbitan monooleate), electrolytes (suchas, but not limited to, sodium chloride, potassium chloride or sodiumbicarbonate) or sequestering agents (such as, but not limited to, EDTA(ethylene diamine tetraacetic acid and the salts thereof)).

A pH stabilizer such as citric acid may be optionally added to the tastemasked liquid pharmaceutical composition of the present invention tostabilize pH and prevent microbial growth. Citric acid is advantageouslyadded since a lower pH will prevent microbial growth and add to thestability of the product.

A pH buffer may be optionally added to the taste masked liquidpharmaceutical composition of the present invention to maintain pH in adesired range or to enhance the solubility of the pharmaceuticallyactive agent. Suitable buffers are those that are not chemicallyreactive with other ingredients and are present in amounts sufficient toprovide the desired degree of pH buffering.

When the taste masked liquid pharmaceutical composition is a suspension,the solubility of the pharmaceutically active agent is reduced bymaintaining pH in a range of from about pH 6 to about pH 8; preferably,about pH 7. Preferably, a buffer is optionally present in a suspensionin a range of up to about 1 gram per 100 mL. More preferably, a bufferis not present in a suspension since the pharmaceutically active agent(in particular, levofloxacin) acts as an autobuffering agent tostabilize pH at about pH 7.

When the taste masked liquid pharmaceutical composition is a solution,the solubility of the pharmaceutically active agent is increased bymaintaining pH in a range of from about pH 3 to about pH 6; preferably,about pH 5. Preferably, a buffer is present in a solution in a range offrom 0.01 to 1 gram per 100 mL.

Wetting agents may be employed in the taste masked liquid pharmaceuticalcomposition to facilitate the dispersion of hydrophobic pharmaceuticallyactive agents. Preferably, a minimal concentration of wetting agentsshould be selected to achieve optimum dispersion of the pharmaceuticallyactive agent. It should be appreciated that an excess concentration ofwetting agent may cause flocculation. Those skilled in the art are wellversed in suitable empirical methods to determine the appropriatewetting agents and concentrations to achieve optimum dispersion andavoid flocculation. Suitable wetting agents are listed in the U.S.Pharmacoepia XXI.

Preservatives useful in the present invention include but are notlimited to sodium benzoate, potassium sorbate, salts of edetate (alsoknown as salts of ethylenediaminetetraacetic acid, or EDTA, such asdisodium edetate), parabens (such as methyl, ethyl, propyl and butylp-hydroxybenzoic acids esters or mixtures thereof) or mixtures thereof.The preservatives listed above are exemplary, but each preservative mustbe evaluated on an empirical basis, in each composition, to assure thecompatibility and efficacy of the preservative. Methods for evaluatingthe efficacy of preservatives in liquid pharmaceutical compositions areknown to those skilled in the art. Sodium benzoate, propylparaben,butylparaben or mixtures thereof are preferred preservative ingredientsand may be added to a taste masked liquid pharmaceutical compositionalthough other pharmaceutically acceptable preservatives may besubstituted therefor.

Preservatives may be present in amounts of up to about 1 gram per 100mL. Preferably, an individual preservative may be present in an amountin the range of from about 0.015 to about 0.5 gram per 100 mL.Preferably, a preservative such as propylparaben, butylparaben ormixtures thereof is present in a range of from about 0.01 to about 0.05gram per 100 mL. More preferably, about 0.006 gram per 100 mL of apreservative selected from propylparaben, butylparaben or mixturesthereof is present.

A preservative such as sodium benzoate may be optionally present in arange of from about 0.1 to about 0.5 gram per 100 mL. More preferably,about 0.2 gram per 100 mL sodium benzoate is present.

Coloring agents also may be incorporated to provide an appealing colorto the taste masked liquid pharmaceutical composition. Suitable coloringagents are well known to those skilled in the art and are those thatavoid chemical incompatibilities with other ingredients.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given with theunderstanding that these examples are intended only to be illustrationswithout serving as a limitation on the scope of the present invention.

Several embodiments of the present liquid pharmaceutical compositioncomprising an antibiotic and a taste masking composition are hereinprovided wherein the solution or suspension has superior taste maskingcharacteristics and is stable and pourable.

EXAMPLE 1 Manufacturing Procedure for a Taste Masked LiquidPharmaceutical Suspension

Using the appropriate equipment and conditions for the desired batchsize, a taste masked pharmaceutical suspension is prepared as follows:

-   1. Add the liquid ingredients (except glycerin) and an appropriate    amount of purified water in a first container;-   2. Mix the liquids with an appropriate mixer;-   3. Add the dry ingredients (except xanthan gum) and the    pharmaceutically active agent to the mixed liquid portion;-   4. Mix the liquid portion and dry ingredients with an appropriate    mixer;-   5. Prepare a xanthan gum-glycerin slurry by placing the glycerin in    a second container, adding xanthan gum and dispersing the xanthan    gum with an appropriate mixer;-   6. Transfer the xanthan gum-glycerin slurry to the first container    and mix with an appropriate mixer for an appropriate amount of time;-   7. Add the flavoring and coloring agents to the first container and    mix with an appropriate mixer;-   8. Add purified water as needed to bring the batch to the final    batch weight; and,-   9. Mix the ingredients, slurry and agents for an appropriate amount    of time, thereby forming the suspension.

EXAMPLE 2a Manufacturing Procedure for a Taste Masked LiquidPharmaceutical Solution

Using the appropriate equipment and conditions for the desired batchsize, a taste masked pharmaceutical solution is prepared as follows:

-   1. Add a sorbitol solution and an appropriate amount of purified    water in a first container;-   2. Mix the sorbitol solution and water with an appropriate mixer;-   3. Prepare a paraben-glycerin slurry by placing the glycerin in a    second container, adding butylparaben and propylparaben and    dispersing the parabens with an appropriate mixer;-   4. Transfer the paraben-glycerin slurry to the first container and    mix with an appropriate mixer for an appropriate amount of time;-   5. Add the remaining liquid ingredients to the first container and    mix with an appropriate mixer for an appropriate amount of time;-   6. Add the dry ingredients and the pharmaceutically active agent to    the first container and mix with an appropriate mixer for an    appropriate amount of time;-   7. Add the flavoring and coloring agents to the first container and    mix with an appropriate mixer;-   8. Adjust pH to a desired value as needed by adding an appropriate    acid or base;-   9. Add purified water as needed to bring the batch to the final    batch weight; and,-   10. Mix the ingredients, slurry and agents for an appropriate amount    of time, thereby forming the solution.

EXAMPLE 2b Manufacturing Procedure for a Taste Masked LiquidPharmaceutical Solution

Using the appropriate equipment and conditions for the desired batchsize, an alternative method for preparing a taste masked pharmaceuticalsolution is as follows:

-   1. Add an appropriate amount of purified water in a first container;-   2. Add sucrose and sucralose to the first container and mix with an    appropriate mixer for an appropriate amount of time;-   3. Prepare a paraben-glycerin slurry by placing the glycerin in a    second container, adding butylparaben and propylparaben and    dispersing the parabens with an appropriate mixer;-   4. Transfer the paraben-glycerin slurry to the first container and    mix with an appropriate mixer for an appropriate amount of time;-   5. Add an appropriate amount of purified water to a third container    and adjust pH to a desired acidic value as needed by adding an    appropriate acid to the third container;-   6. Transfer the acidified water to the first container and mix with    an appropriate mixer for an appropriate amount of time;-   7. Add the pharmaceutically active agent to the first container and    mix with an appropriate mixer for an appropriate amount of time;-   8. Add the flavoring and coloring agents to the first container and    mix with an appropriate mixer;-   9. Add purified water as needed to bring the batch to the final    batch weight; and,-   10. Mix the ingredients, slurry and agents for an appropriate amount    of time, thereby forming the solution.

EXAMPLE 3 Taste Masked Suspension Ingredient Ranges

The ranges for the components used in preferred embodiments of the tastemasked pharmaceutical composition of the present invention, wherein thecomposition comprises a suspension are indicated as follows:Quantitative Composition of a Suspension (250 mg/5 mL) Component Range %W/V Levofloxacin Hemihydrate   1-5.2 Glycerin, USP 2.5-20  Sucrose,Extra Fine Granular NF 10-60 High Fructose Corn Syrup 55% 20-75 SorbitolSolution, USP 10-70 Purified Water  5-25 Microcrystalline Cellulose andSodium 0.1-1.4 Carboxymethyl Cellulose, NF Sodium Benzoate, NF 0.01-0.5 Propylparaben, NF 0.01-0.03 Butylparaben, NF 0.006-0.05  Citric Acid,Anhydrous USP 0.005-1.0  Sucralose NF (pure substance, not marketed)0.05-2.5  Xanthan Gum USP, EP, JPE 0.05-0.25 Flavoring Agent(s)0.02-0.06 Debittering Agent(s) 0.0-1.0 Sweetening Agent(s)  0.0-121.5Purified Water (bring to 100% w/v) as needed

EXAMPLES 4-11 Taste Masked Suspensions

Embodiments of the present invention are herein described, wherein ataste masked liquid pharmaceutical suspension comprises levofloxacin anda taste masking effective amount of an artificial sweetener.

EXAMPLE 4

Quantitative Composition of a Levofloxacin Liquid Suspension (250 mg/5mL) Component % W/V Levofloxacin Hemihydrate 5.123 Glycerin, USP 10Sucrose, Extra Fine Granular NF 20 High Fructose Corn Syrup 55% 50Sorbitol Solution, USP 20 Purified Water 15 Microcrystalline Celluloseand Sodium 0.7 Carboxymethyl Cellulose, NF Sodium Benzoate, NF 0.2Propylparaben, NF 0.015 Citric Acid, Anhydrous USP 0.075 Sucralose NF(pure substance, not marketed) 1.02 Xanthan Gum USP, EP, JPE 0.12Peppermint Flavor 0.03 Purified Water (qs to 100% w/v) as needed

EXAMPLE 5

Quantitative Composition of a Levofloxacin Liquid Suspension (125 mg/5mL) Component % W/V Levofloxacin Hemihydrate 2.5615 Glycerin, USP 10Sucrose, Extra Fine Granular NF 20 High Fructose Corn Syrup 55% 50Sorbitol Solution, USP 20 Purified Water 15 Microcrystalline Celluloseand Sodium 0.7 Carboxymethyl Cellulose, NF Butylparaben, NF 0.020Propylparaben, NF 0.030 Citric Acid, Anhydrous USP 0.075 Sucralose NF(pure substance, not marketed powder) 1.02 Xanthan Gum USP, EP, JPE 0.12Lemon Flavor 0.05 Peppermint Flavor 0.04 Purified Water (qs to 100% w/v)as needed

EXAMPLE 6

Quantitative Composition of a Levofloxacin Liquid Suspension (250 mg/5mL) Component % W/V Levofloxacin Hemihydrate 5.123 Glycerin, USP 10Sucrose, Extra Fine Granular NF 20 High Fructose Corn Syrup 55% 50Sorbitol Solution, USP 20 Purified Water 15 Microcrystalline Celluloseand Sodium Carboxymethyl 0.7 Cellulose, NF Butylparaben, NF 0.02Propylparaben, NF 0.03 Citric Acid, Anhydrous USP 0.075 Sucralose NF(pure substance, not marketed powder) 1.02 Xanthan Gum USP, EP, JPE 0.12Artificial Vanilla Mint Flavor 0.04 Natural Taste Masker Compound 0.04Purified Water (qs to 100% w/v) as needed

EXAMPLE 7

Quantitative Composition of a Levofloxacin Liquid Suspension (250 mg/5mL) Component % W/V Levofloxacin Hemihydrate 5.123 Glycerin, USP 10Sucrose, Extra Fine Granular NF 20 High Fructose Corn Syrup 55% 50Sorbitol Solution, USP 20 Microcrystalline Cellulose and SodiumCarboxymethyl 0.7 Cellulose, NF Butylparaben, NF 0.02 Propylparaben, NF0.03 Citric Acid, Anhydrous USP 0.075 Sucralose NF (pure substance, notmarketed powder) 1.02 Xanthan Gum USP, EP, JPE 0.12 Peppermint Flavor0.3 Purified Water (qs to 100% w/v) as needed

EXAMPLE 8

Quantitative Composition of a Levofloxacin Liquid Suspension (250 mg/5mL) Component % W/V Levofloxacin Hemihydrate 5.123 Glycerin, USP 10Sucrose, Extra Fine Granular NF 20 High Fructose Corn Syrup 55% 50Sorbitol Solution, USP 20 Purified Water 15 Microcrystalline Celluloseand Sodium Carboxymethyl 0.7 Cellulose, NF Butylparaben, NF 0.02Propylparaben, NF 0.03 Citric Acid, Anhydrous USP 0.075 Sucralose NF(pure substance, not marketed powder) 1.02 Xanthan Gum USP, EP, JPE 0.12Artificial Chocolate Flavor 0.05 Peppermint Flavor 0.03 Natural TasteMasker Compound 0.04 Purified Water (qs to 100% w/v) as needed

EXAMPLE 9

Quantitative Composition of a Levofloxacin Liquid Suspension (250 mg/5mL) Component % W/V Levofloxacin Hemihydrate 5.123 Glycerin, USP 10Sucrose, Extra Fine Granular NF 20 High Fructose Corn Syrup 55% 50Sorbitol Solution, USP 20 Purified Water 15 Microcrystalline Celluloseand Sodium Carboxymethyl 0.7 Cellulose, NF Butylparaben, NF 0.02Propylparaben, NF 0.03 Citric Acid, Anhydrous USP 0.075 Sucralose NF(pure substance, not marketed powder) 1.02 Xanthan Gum USP, EP, JPE 0.12Artificial Cherry Flavor 0.04 Peppermint Flavor 0.03 Artificial TasteMasker Compound 0.04 Purified Water (qs to 100% w/v) as needed

EXAMPLE 10

Quantitative Composition of a Levofloxacin Liquid Suspension (250 mg/5mL) Component % W/V Levofloxacin Hemihydrate 5.123 Glycerin, USP 10Sucrose, Extra Fine Granular NF 20 High Fructose Corn Syrup 55% 50Sorbitol Solution, USP 20 Purified Water 15 Microcrystalline Celluloseand Sodium Carboxymethyl 0.7 Cellulose, NF Butylparaben, NF 0.02Propylparaben, NF 0.03 Citric Acid, Anhydrous USP 0.075 Sucralose NF(pure substance, not marketed powder) 1.02 Xanthan Gum USP, EP, JPE 0.12Artificial Bubblegum Flavor 0.045 Peppermint Flavor 0.04 Natural TasteMasker Compound 0.04 Purified Water (qs to 100% w/v) as needed

EXAMPLE 11

Quantitative Composition of a Levofloxacin Liquid Suspension (250 mg/5mL) Component % W/V Levofloxacin Hemihydrate 5.123 Glycerin, USP 10Sucrose, Extra Fine Granular NF 20 High Fructose Corn Syrup 55% 50Sorbitol Solution, USP 20 Purified Water 15 Microcrystalline Celluloseand Sodium Carboxymethyl 0.7 Cellulose, NF Butylparaben, NF 0.02Propylparaben, NF 0.03 Citric Acid, Anhydrous USP 0.075 Sucralose NF(pure substance, not marketed powder) 1.02 Xanthan Gum USP, EP, JPE 0.12Natural & Artificial Lemon Flavor 0.04 Peppermint Flavor 0.045 NaturalTaste Masker Compound 0.04 Purified Water (qs to 100% w/v) as needed

EXAMPLE 12 Taste Masked Solution Ingredient Ranges

The ranges for the components used in preferred embodiments of the tastemasked pharmaceutical composition of the present invention, wherein thecomposition comprises a solution are indicated as follows: QuantitativeComposition of a Solution (250 mg/5 mL) Component % W/V LevofloxacinHemihydrate 2.5615 Hydrochloric Acid (0.1 mL HCl 6 N) as needed Sucrose,Extra Fine Granular NF 20-50 Sucralose NF (pure substance, not marketed)0.05-1.5  Maltitol Solution (a blend of Hydrogenated Starch 10-60Hydrolysate 75% w/w solids) NF Sorbitol Solution, USP 10-70 Glycerin,USP 2.5-20  Purified Water  5-25 Methylparaben, NF 0.08-0.3 Propylparaben, NF 0.01-0.03 Butylparaben, NF 0.006-0.05  PeppermintFlavor 0.04-0.08 Bubblegum Flavor 0.04-0.06 Special Taste MaskerCompound 0.04-0.06 Purified Water (qs to 100% w/v) as needed

EXAMPLES 13-17 Taste Masked Solutions

Embodiments of the present invention are herein described, wherein ataste masked liquid pharmaceutical solution comprises levofloxacin and ataste masking effective amount of an artificial sweetener.

EXAMPLE 13

Quantitative Composition of a Levofloxacin Liquid Solution (125 mg/5 mL)Component % W/V Levofloxacin Hemihydrate 2.5615 Glycerin, USP 10Sucrose, Extra Fine Granular NF 20 Maltitol Solution (a blend ofHydrogenated Starch 50 Hydrolysate 75% w/w solids) NF Sorbitol Solution,USP 20 Purified Water 17 Butylparaben, NF 0.02 Propylparaben, NF 0.03Sucralose NF (pure substance, not marketed) 1.02 Peppermint Flavor 0.04Bubblegum Flavor 0.04 Special Taste Masker Compound 0.04 Purified Water(qs to 100% w/v) 100

Example 14

Quantitative Composition of a Levofloxacin Liquid Solution (125 mg/5 mL)Component % W/V Levofloxacin Hemihydrate 2.5615 Glycerin, USP 10Sucrose, Extra Fine Granular NF 20 High Fructose Corn Syrup 55% 50Sorbitol Solution, USP 20 Purified Water 17 Butylparaben, NF 0.02Propylparaben, NF 0.03 Sucralose NF (pure substance, not marketed) 1.02Purified Water (qs to 100% w/v) 100

EXAMPLE 15

Quantitative Composition of a Levofloxacin Liquid Solution (125 mg/5 mL)Component % W/V Levofloxacin Hemihydrate 2.5615 Hydrochloric Acid (0.1mL HCl 6N) as needed Sucrose 50 Sucralose NF (pure substance, notmarketed) 0.5 Glycerin, USP 10 Methylparaben, NF 0.18 Propylparaben, NF0.02 Peppermint Flavor 0.04 Bubblegum Flavor 0.04 Special Taste MaskerCompound 0.05 Purified Water (qs to 100% w/v) as needed

EXAMPLE 16

Quantitative Composition of a Levofloxacin Liquid Solution (125 mg/5 mL)Component % W/V Levofloxacin Hemihydrate 2.5615 Hydrochloric Acid (0.1mL HCl 6N) as needed Sucrose 50 Sucralose NF (pure substance, notmarketed) 0.8 Glycerin, USP 10 Methylparaben, NF 0.18 Propylparaben, NF0.02 Peppermint Flavor 0.05 Bubblegum Flavor 0.06 Special Taste MaskerCompound 0.05 Purified Water (qs to 100% w/v) as needed

EXAMPLE 17

Quantitative Composition of a Levofloxacin Liquid Solution (125 mg/5 mL)Component % W/V Levofloxacin Hemihydrate 2.5615 Hydrochloric Acid (0.1mL HCl 6N) as needed Sucrose 50 Sucralose NF (pure substance, notmarketed) 0.8 Glycerin, USP 10 Methylparaben, NF 0.18 Propylparaben, NF0.02 Peppermint Flavor 0.08 Bubblegum Flavor 0.06 Special Taste MaskerCompound 0.05 Purified Water (qs to 100% w/v) as needed

1-84. (canceled)
 85. A taste masked liquid pharmaceutical compositioncomprising a bitter tasting pharmaceutically active agent and a tastemasking composition, said taste masking composition comprising anartificial sweetener, a sugar sweetener and a flavoring agent.
 86. Theliquid pharmaceutical composition of claim 85 wherein the bitter tastingpharmaceutically active agent is an antibiotic selected from the groupconsisting of a naphthyridone-carboxylic acid type antibiotic, aquinolone-carboxylic acid type antibiotic, a cephalosporin typeantibiotic, a macrolide type antibiotic and a penicillin typeantibiotic.
 87. The liquid pharmaceutical composition of claim 85wherein the artificial sweetener is selected from the group consistingof aspartame, acesulfame potassium, cyclamate, saccharin, saccharinsodium and sucralose and mixtures thereof.
 88. The liquid pharmaceuticalcomposition of claim 85 wherein the sugar sweetener is selected from thegroup consisting of monosaccharides, disaccharides or polysaccharides(selected from xylose, ribose, glucose, mannose, galactose, fructose,dextrose, sucrose or maltose), high fructose corn syrup, maltitol syrup,partially hydrolyzed starch, corn syrup solids, sugar alcohols (selectedfrom sorbitol, xylitol, mannitol or glycerin) and combinations thereof.89. The liquid pharmaceutical composition of claim 85 wherein theflavoring agent is selected from the group consisting of naturalflavors, natural fruit flavors, artificial flavors, artificial fruitflavors and flavor enhancers or mixtures thereof.